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Clinical Trial Results:
A Phase III, Open Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Compared With a Platinum Agent (Cisplatin or Carboplatin) in Combination With Either Pemetrexed or Gemcitabine for PD-L1-Selected, Chemotherapy-Naive Patients With Stage IV Non-Squamous Or Squamous Non-Small Cell Lung Cancer

Summary
EudraCT number	2014-003083-21
Trial protocol	DE HU CZ ES GR FR PL IT
Global end of trial date	08 Mar 2022

Results information
Results version number	v2(current)
This version publication date	05 Mar 2023
First version publication date	14 Feb 2021
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GO29431

ISRCTN number

US NCT number

NCT02409342

WHO universal trial number (UTN)

Other trial identifiers

Other Sponsor ID: IMpower110

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Mar 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Mar 2022

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial was to evaluate the safety and efficacy of atezolizumab compared with chemotherapy consisting of a platinum agent (cisplatin or carboplatin per investigator discretion) combined with either pemetrexed (non-squamous disease) or gemcitabine (squamous disease) in PD-L1-selected, chemotherapy-naïve patients with Stage IV Non-Small Cell Lung Cancer.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Jul 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

34 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 31

Country: Number of subjects enrolled

China: 3

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Spain: 35

Country: Number of subjects enrolled

France: 27

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Greece: 32

Country: Number of subjects enrolled

Hungary: 26

Country: Number of subjects enrolled

Italy: 46

Country: Number of subjects enrolled

Japan: 51

Country: Number of subjects enrolled

Korea, Republic of: 11

Country: Number of subjects enrolled

Poland: 51

Country: Number of subjects enrolled

Romania: 54

Country: Number of subjects enrolled

Russian Federation: 50

Country: Number of subjects enrolled

Serbia: 42

Country: Number of subjects enrolled

Thailand: 14

Country: Number of subjects enrolled

Turkey: 36

Country: Number of subjects enrolled

Ukraine: 26

Country: Number of subjects enrolled

United States: 16

Worldwide total number of subjects

572

EEA total number of subjects

279

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

289

From 65 to 84 years

281

85 years and over

Subject disposition

Top of page

Recruitment details

Recruitment included: Japan, Spain, Greece, Italy, Brazil, Russian, France, United States of America, Ukraine, Romania, Turkey, Poland, Serbia, Hungary, Thailand, Great Britain, Republic of Korea, Germany, China.

Screening details

Only participants who are PD-L1-selected chemotherapy-naive with Stage IV non-small cell lung cancer (NSCLC) were enrolled.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy

Arm description

Participants with non-squamous NSCLC will receive chemotherapy with pemetrexed in combination with either cisplatin or carboplatin (per investigator discretion) on Day 1 of each 21-day cycle for 4 or 6 cycles as per local standard of care, followed by maintenance therapy with pemetrexed alone as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months). Participants with squamous NSCLC will receive chemotherapy with gemcitabine on Days 1 and 8 of each 21-day cycle in combination with either cisplatin or carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles as per local standard of care, followed by best supportive care as per local standard of care until disease progression, unacceptable toxicity, or death (maximum up to approximately 58 months).

Arm type

Active comparator

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin will be administered as intravenous infusion at a dose of area under the concentration-time curve (AUC) 6 when given in combination with pemetrexed or at a dose of AUC 5 when given in combination with gemcitabine, every 21 days for 4 or 6 cycles as per local standard of care.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pemetrexed will be administered as intravenous infusion at a dose of 500 mg/m^2 on Day 1 of each 21-day cycle as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months).

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine will be administered as intravenous infusion at a dose of 1250 mg/m^2 (in combination with cisplatin) or 1000 mg/m^2 (in combination with carboplatin), on Days 1 and 8 of each 21-day cycle for 4 or 6 cycles as per local standard of care.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin will be administered as intravenous infusion at a dose of 75 mg per meter squared (mg/m^2) every 21 days for 4 or 6 cycles as per local standard of care.

Atezolizumab

Arm description

Participants with squamous or non-squamous NSCLC will receive atezolizumab on Day 1 of each 21-day cycle until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months).

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq, MPDL3280A, RO5541267

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab 1200 milligram (mg) will be administered as intravenous infusion every 21 days until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months).

Number of subjects in period 1	Chemotherapy	Atezolizumab
Started	287	285
Completed	0	0
Not completed	287	285
Participant Moved Into Roll-Over Study	-	2
Consent withdrawn by subject	24	17
Local ethics requires subjects' data be removed.	-	1
Study Terminated By Sponsor	48	59
Death	211	201
Sponsor Decision	1	-
Lost to follow-up	3	5

Baseline characteristics

Top of page

Reporting group title

Chemotherapy

Reporting group description

Reporting group title

Atezolizumab

Reporting group description

Reporting group values	Chemotherapy	Atezolizumab	Total
Number of subjects	287	285	572
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	140	149	289
From 65-84 years	145	136	281
85 years and over	2	0	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	63.8 ( 8.8 )	63.1 ( 8.8 )	-
Sex: Female, Male
Units:
Female	89	87	176
Male	198	198	396
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	33	48	81
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	2	2	4
White	247	232	479
More than one race	0	1	1
Unknown or Not Reported	5	2	7
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	14	21	35
Not Hispanic or Latino	265	262	527
Unknown or Not Reported	8	2	10

End points

Top of page

Reporting group title

Chemotherapy

Reporting group description

Reporting group title

Atezolizumab

Reporting group description

Subject analysis set title

Chemotherapy Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Chemotherapy in the safety-evaluable participants.

Subject analysis set title

Atezolizumab Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Atezolizumab in the safety-evaluable participants.

Primary: Overall Survival (OS) in the TC3 or IC3-WT Populations

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End point title

Overall Survival (OS) in the TC3 or IC3-WT Populations

End point description

OS is defined as the time from randomization to death from any cause. Note: 999999=not estimable.

End point type

Primary

End point timeframe

From randomization to death from any cause until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	98	107
Units: Months
median (confidence interval 95%)
TC3 or IC3-WT Population	13.1 (7.4 to 16.5)	20.2 (16.5 to 999999)

OS Statistical Analysis

Statistical analysis description

TC3 or IC3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0106

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.595

Confidence interval

level

95%

sides

2-sided

lower limit

0.398

upper limit

0.89

Notes
[1] - Stratified analysis. OS was tested hierarchically in the efficacy analysis populations, first TC3 or IC3-WT then TC2/3 or IC2/3-WT and the TC1/2/3 or IC1/2/3-WT population.

Primary: Overall Survival (OS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

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End point title

Overall Survival (OS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

End point description

OS is defined as the time from randomization to death from any cause. Note: n=participants with data at given timepoint. 999999=not estimable.

End point type

Primary

End point timeframe

From randomization to death from any cause until data cut-off on 4 February 2020 (up to approximately 54.5 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	277	277
Units: Months
median (confidence interval 95%)
TC2/3 or IC2/3-WT Population (n=162, n=166)	16.1 (12.6 to 18.0)	19.9 (17.2 to 25.3)
TC1/2/3 or IC1/2/3-WT Population (n=277, n=277)	14.7 (11.2 to 16.5)	18.9 (13.4 to 23.0)

OS Statistical Analysis

Statistical analysis description

TC1/2/3 or IC/1/2/3-WT

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.107 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.845

Confidence interval

level

95%

sides

2-sided

lower limit

0.688

upper limit

1.037

Notes
[2] - Stratified analysis. OS was tested hierarchically in the efficacy analysis populations.
[3] - P-value is descriptive as it was not formally tested.

OS Statistical Analysis

Statistical analysis description

TC2/3 or IC2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.3091

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.868

Confidence interval

level

95%

sides

2-sided

lower limit

0.661

upper limit

1.14

Notes
[4] - Stratified analysis. OS was tested hierarchically in the efficacy analysis populations.

Secondary: Progression-free Survival (PFS) in the TC3 or IC3-WT Populations

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End point title

Progression-free Survival (PFS) in the TC3 or IC3-WT Populations

End point description

PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first.

End point type

Secondary

End point timeframe

From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	98	107
Units: Months
number (confidence interval 95%)
TC3 or IC3-WT Population	5.0 (4.2 to 5.7)	8.1 (6.8 to 11.0)

PSF Statistical Analysis

Statistical analysis description

TC3 or IC3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.007 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.449

upper limit

0.884

Notes
[5] - Stratified Analysis
[6] - P-value is descriptive as it was not formally tested.

Secondary: Progression-free Survival (PFS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

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End point title

Progression-free Survival (PFS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

End point description

End point type

Secondary

End point timeframe

From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 4 February 2020 (up to approximately 54.5 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	277	277
Units: Months
number (confidence interval 95%)
TC2/3 or IC2/3-WT Population (n=162, n=166)	5.5 (4.5 to 5.7)	7.3 (5.6 to 9.3)
TC1/2/3 or IC1/2/3-WT Population (n=277, n=277)	5.6 (4.7 to 5.7)	5.8 (5.5 to 7.3)

PFS Statistical Analysis

Statistical analysis description

TC1/2/3 or IC1/2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.0004 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.716

Confidence interval

level

95%

sides

2-sided

lower limit

0.595

upper limit

0.863

Notes
[7] - Stratified Analysis
[8] - P-value is descriptive as it was not formally tested.

PFS Statistical Analysis

Statistical analysis description

TC2/3 or IC2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.0004 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.641

Confidence interval

level

95%

sides

2-sided

lower limit

0.501

upper limit

0.82

Notes
[9] - Stratified Analysis
[10] - P-value is descriptive as it was not formally tested.

Secondary: Percentage of Participants With Objective Response (ORR) in the TC3 or IC3-WT Populations

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End point title

Percentage of Participants With Objective Response (ORR) in the TC3 or IC3-WT Populations

End point description

Objective response (partial response plus complete response) as determined by the investigator according to RECIST v1.1.

End point type

Secondary

End point timeframe

Every 6 weeks for 48 weeks following Day 1, thereafter every 9 weeks after completion of Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression until data cut-off on 10 Sep 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	98	107
Units: Percentage of participants
number (not applicable)
TC3 or IC3-WT Population	28.6	38.3

ORR Statistical Analysis

Statistical analysis description

TC3 or IC3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

Method

Parameter type

Difference in ORR

Point estimate

9.75

Confidence interval

level

95%

sides

2-sided

lower limit

-4.07

upper limit

23.56

Notes
[11] - Stratified Analysis

Secondary: Percentage of Participants With Objective Response (ORR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

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End point title

Percentage of Participants With Objective Response (ORR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

End point description

Objective response (partial response plus complete response) as determined by the investigator according to RECIST v1.1. Note: n=participants with data at given timepoint.

End point type

Secondary

End point timeframe

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	277	277
Units: Percentage of participants
number (not applicable)
TC2/3 or IC2/3-WT Population (n=162, n=166)	32.1	33.7
TC1/2/3 or IC1/2/3-WT Population (n=277, n=277)	32.1	31.4

ORR Statistical Analysis

Statistical analysis description

TC1/2/3 or IC1/2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

Method

Parameter type

Difference in ORR

Point estimate

-0.72

Confidence interval

level

95%

sides

2-sided

lower limit

-8.84

upper limit

7.39

Notes
[12] - Stratified analysis

ORR Statistical Analysis

Statistical analysis description

TC2/3 or IC2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

Method

Parameter type

Difference in ORR

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

-9.14

upper limit

12.42

Notes
[13] - Stratified analysis

Secondary: Duration of Response (DOR) in the TC3 or IC3-WT Populations

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End point title

Duration of Response (DOR) in the TC3 or IC3-WT Populations

End point description

DOR is defined as the time from the first occurrence of a documented objective response to the time of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first. Note: 999999=not estimable

End point type

Secondary

End point timeframe

From first occurrence of a complete response or partial response, whichever occurs first, until first date that progressive disease or death is documented, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	28	41
Units: Months
number (confidence interval 95%)
TC3 or IC3-WT Population	6.7 (5.5 to 17.3)	999999 (11.8 to 999999)

DOR Statistical Analysis

Statistical analysis description

TC3 or IC3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.365

Confidence interval

level

95%

sides

2-sided

lower limit

0.166

upper limit

0.8

Notes
[14] - Stratified Analysis

Secondary: Duration of Response (DOR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Top of page

End point title

Duration of Response (DOR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

End point description

End point type

Secondary

End point timeframe

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	89	87
Units: Months
number (confidence interval 95%)
TC2/3 or IC2/3-WT Population (n=52, n=56)	5.8 (5.1 to 9.8)	38.9 (16.9 to 999999)
TC1/2/3 or IC1/2/3-WT Population (n=89, n=87)	5.7 (5.1 to 8.8)	26.3 (16.1 to 43.7)

DOR Statistical Analysis

Statistical analysis description

TC1/2/3 or IC1/2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.284

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

0.424

Notes
[15] - Stratified analysis

DOR Statistical Analysis

Statistical analysis description

TC2/3 or IC2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.235

Confidence interval

level

95%

sides

2-sided

lower limit

0.135

upper limit

0.409

Notes
[16] - Stratified analysis

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC3 or IC3-WT Populations

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End point title

Percentage of Participants Who are Alive at 1 and 2 Years in the TC3 or IC3-WT Populations

End point description

End point type

Secondary

End point timeframe

Baseline to 2 years or death, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	98	107
Units: Percentage of participants
number (confidence interval 95%)
1-Year TC3 or IC3-WT (n=98; n=107)	50.64 (40.00 to 61.27)	64.90 (55.36 to 74.43)
2-Year TC3 or IC3-WT (n=98; n=107)	24.79 (13.11 to 36.47)	45.49 (32.11 to 58.88)

% of Participants Alive Statistical Analysis

Statistical analysis description

2-Year TC3 or IC3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Event Free Rate

Point estimate

20.7

Confidence interval

level

95%

sides

2-sided

lower limit

2.94

upper limit

38.47

% of Participants Alive Statistical Analysis

Statistical analysis description

1-Year TC3 or IC3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Event Free Rate

Point estimate

14.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

28.55

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC2/3 or IC2/3-WT Populations

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End point title

Percentage of Participants Who are Alive at 1 and 2 Years in the TC2/3 or IC2/3-WT Populations

End point description

Note: n=participants with data at given timepoint.

End point type

Secondary

End point timeframe

Baseline to 2 years or death, whichever occurs firstuntil clinical cut-off date on 4 February 2020 (up to approximately 54.5 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	162	166
Units: Percentage of participants
number (confidence interval 95%)
1-Year TC2/3 or IC2/3-WT (n=162; n=166)	58.65 (50.95 to 66.35)	63.39 (56.00 to 70.77)
2-Year TC2/3 or IC2/3-WT (n=162; n=166)	35.42 (27.91 to 42.94)	44.15 (36.51 to 51.80)

% of Participants Alive Statistical Analysis

Statistical analysis description

2-Year TC2/3 or IC2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Event Free Rate

Point estimate

8.73

Confidence interval

level

95%

sides

2-sided

lower limit

-1.99

upper limit

19.45

% of Participants Alive Statistical Analysis

Statistical analysis description

1-Year TC2/3 or IC2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Event Free Rate

Point estimate

4.74

Confidence interval

level

95%

sides

2-sided

lower limit

-5.93

upper limit

15.4

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC1/2/3 or IC1/2/3-WT Populations

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End point title

Percentage of Participants Who are Alive at 1 and 2 Years in the TC1/2/3 or IC1/2/3-WT Populations

End point description

Note: n=participants with data at given timepoint.

End point type

Secondary

End point timeframe

Baseline to 2 years or death, whichever occurs firstuntil clinical cut-off date on 4 February 2020 (up to approximately 54.5 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	277	277
Units: Percentage of participants
number (confidence interval 95%)
1-Year TC1/2/3 or IC1/2/3-WT (n=277; n=277)	54.89 (48.93 to 60.4)	59.95 (54.12 to 65.78)
2-Year TC1/2/3 or IC1/2/3-WT (n=277; n=277)	30.82 (25.28 to 36.36)	41.76 (35.84 to 47.67)

% of Participants Alive Statistical Analysis

Statistical analysis description

2-Year TC1/2/3 or IC1/2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Event Free Rate

Point estimate

10.94

Confidence interval

level

95%

sides

2-sided

lower limit

2.83

upper limit

19.04

% of Participants Alive Statistical Analysis

Statistical analysis description

1-Year TC1/2/3 or IC1/2/3-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

554

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Event Free Rate

Point estimate

5.06

Confidence interval

level

95%

sides

2-sided

lower limit

-3.27

upper limit

13.4

Secondary: Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Score as Assessed by the Symptoms in Lung Cancer (SILC) Scale Symptom Score in the TC3 or IC3-WT Populations

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End point title

Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Score as Assessed by the Symptoms in Lung Cancer (SILC) Scale Symptom Score in the TC3 or IC3-WT Populations

End point description

TTD in each of the patient-reported lung cancer symptoms with use of the SILC scale. The SILC scale is a nine-item content valid self-report measure of lung cancer symptoms. It measures severity of cough, dyspnea, and chest pain with a total symptom severity score. Each SILC symptom scale (dyspnea, cough, chest pain) score was calculated as the average of the component items (range 0 to 4). An increase in score suggested worsening in symptomatology. A symptom score change of 0.3 points for the dyspnea and cough scores was considered to be clinically significant; whereas a symptom score change of 0.5 points for the chest pain score was considered to be clinically significant. Note: n=participants with data at given timepoint. 999999=not estimable.

End point type

Secondary

End point timeframe

Baseline until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	98	107
Units: Months
median (confidence interval 95%)
Cough (n=98, n=107)	3.4 (1.3 to 12.4)	3.5 (1.0 to 10.8)
Dyspnea (n=98, n=107)	1.0 (0.5 to 1.9)	1.3 (0.7 to 3.6)
Chest pain (n=98, n=107)	1.1 (0.7 to 999999)	1.7 (0.7 to 4.5)

TTD Statistical Analysis

Statistical analysis description

Cough in TC3 or IC3-WT Populations

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.142

Confidence interval

level

95%

sides

2-sided

lower limit

0.657

upper limit

1.984

Notes
[17] - Stratified Analysis

TTD Statistical Analysis

Statistical analysis description

Chest pain in TC3 or IC3-WT Populations

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.229

Confidence interval

level

95%

sides

2-sided

lower limit

0.737

upper limit

2.049

Notes
[18] - Stratified analysis

TTD Statistical Analysis

Statistical analysis description

Dyspnoea in TC3 or IC3-WT Populations

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.891

Confidence interval

level

95%

sides

2-sided

lower limit

0.555

upper limit

1.43

Notes
[19] - Stratified analysis

Secondary: Change From Baseline in Patient-reported Lung Cancer Symptoms Score as Assessed by the SILC Scale Symptom Score in the TC3 or IC3-WT Populations

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End point title

Change From Baseline in Patient-reported Lung Cancer Symptoms Score as Assessed by the SILC Scale Symptom Score in the TC3 or IC3-WT Populations

End point description

Change from baseline in each of the patient-reported lung cancer symptoms (cough, dyspnea, or chest pain) with use of the SILC scale. Note: n=participants with data at given timepoint. 9999=Not available; No participant analysed at given timepoint. 999999=not estimable.

End point type

Secondary

End point timeframe

Baseline until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	52	61
Units: Score on a scale
arithmetic mean (standard deviation)
Chest Pain, Week 1 (n=44, n=47)	0.57 ( 1.23 )	0.31 ( 0.84 )
Chest Pain, Week 2 (n=42, n=48)	0.42 ( 1.13 )	0.33 ( 0.85 )
Chest Pain, Week 3 (n=44, n=49)	0.25 ( 1.26 )	0.43 ( 0.97 )
Chest Pain, Week 4 (n=41, n=49)	0.15 ( 1.21 )	0.43 ( 1.08 )
Chest Pain, Week 5 (n=3*, n=47)	0.27 ( 1.19 )	0.28 ( 1.00 )
Chest Pain, Week 6 (n=33, n=48)	0.30 ( 1.26 )	0.25 ( 0.85 )
Chest Pain, Week 7 (n=30, n=44)	0.23 ( 1.04 )	0.30 ( 0.97 )
Chest Pain, Week 8 (n=29, n=44)	0.17 ( 1.12 )	0.20 ( 0.82 )
Chest Pain, Week 9 (n=31, n=47)	0.27 ( 1.00 )	0.33 ( 1.07 )
Chest Pain, Week 10 (n=30, n=40)	0.30 ( 1.13 )	0.25 ( 1.12 )
Chest Pain, Week 11 (n=29, n=34)	0.26 ( 1.32 )	0.21 ( 0.96 )
Chest Pain, Week 12 (n=32, n=40)	0.22 ( 1.33 )	0.33 ( 0.97 )
Chest Pain, Week 13 (n=28, n=38)	0.07 ( 1.17 )	0.30 ( 1.04 )
Chest Pain, Week 14 (n=28, n=35)	0.07 ( 1.16 )	0.27 ( 0.85 )
Chest Pain, Week 15 (n=30, n=40)	0.10 ( 1.23 )	0.45 ( 1.01 )
Chest Pain, Week 16 (n=25, n=32)	0.00 ( 1.20 )	0.19 ( 0.99 )
Chest Pain, Week 17 (n=27, n=34)	0.22 ( 1.41 )	0.22 ( 1.20 )
Chest Pain, Week 18 (n=23, n=37)	0.11 ( 1.26 )	0.26 ( 0.85 )
Chest Pain, Week 19 (n=22, n=32)	0.11 ( 1.01 )	0.23 ( 0.94 )
Chest Pain, Week 20 (n=22, n=35)	0.20 ( 1.32 )	0.23 ( 0.95 )
Chest Pain, Week 21 (n=18, n=36)	0.03 ( 0.83 )	0.11 ( 0.87 )
Chest Pain, Week 22 (n=20, n=35)	0.30 ( 1.35 )	0.19 ( 1.02 )
Chest Pain, Week 23 (n=16, n=33)	0.00 ( 1.00 )	0.33 ( 0.84 )
Chest Pain, Week 24 (n=16, n=33)	-0.09 ( 0.88 )	0.18 ( 1.13 )
Chest Pain, Week 25 (n=11, n=29)	0.27 ( 0.79 )	0.29 ( 0.87 )
Chest Pain, Week 26 (n=13, n=32)	0.12 ( 1.31 )	0.11 ( 0.72 )
Chest Pain, Week 27 (n=11, n=32)	0.05 ( 1.15 )	0.20 ( 0.80 )
Chest Pain, Week 28 (n=11, n=30)	0.00 ( 0.81 )	0.23 ( 0.98 )
Chest Pain, Week 29 (n=12, n=28)	-0.25 ( 0.87 )	0.18 ( 0.80 )
Chest Pain, Week 30 (n=12, n=30)	0.21 ( 1.45 )	0.32 ( 0.95 )
Chest Pain, Week 31 (n=11, n=29)	0.18 ( 1.72 )	0.33 ( 0.90 )
Chest Pain, Week 32 (n=11, n=23)	0.41 ( 1.61 )	0.35 ( 1.20 )
Chest Pain, Week 33 (n=13, n=26)	0.00 ( 1.44 )	0.04 ( 1.03 )
Chest Pain, Week 34 (n=10, n=26)	0.40 ( 1.31 )	0.31 ( 0.98 )
Chest Pain, Week 35 (n=11, n=27)	0.00 ( 1.16 )	0.28 ( 1.13 )
Chest Pain, Week 36 (n=9, n=25)	0.06 ( 0.85 )	0.08 ( 0.95 )
Chest Pain, Week 37 (n=8, n=23)	0.31 ( 1.25 )	0.39 ( 0.89 )
Chest Pain, Week 38 (n=11, n=21)	0.23 ( 0.72 )	0.31 ( 1.20 )
Chest Pain, Week 39 (n=9, n=22)	0.22 ( 1.00 )	0.14 ( 0.92 )
Chest Pain, Week 40 (n=7, n=23)	0.43 ( 1.02 )	0.30 ( 1.21 )
Chest Pain, Week 41 (n=7, n=20)	0.36 ( 1.07 )	0.30 ( 1.01 )
Chest Pain, Week 42 (n=6, n=20)	0.25 ( 1.04 )	0.33 ( 1.05 )
Chest Pain, Week 43 (n=5, n=20)	0.30 ( 1.15 )	0.18 ( 1.29 )
Chest Pain, Week 44 (n=7, n=19)	0.14 ( 0.99 )	0.42 ( 1.15 )
Chest Pain, Week 45 (n=4, n=21)	0.63 ( 0.48 )	0.31 ( 0.90 )
Chest Pain, Week 46 (n=5, n=19)	0.30 ( 0.45 )	0.37 ( 0.93 )
Chest Pain, Week 47 (n=4, n=18)	0.50 ( 0.71 )	0.31 ( 0.86 )
Chest Pain, Week 48 (n=3, n=15)	0.50 ( 0.50 )	0.17 ( 0.79 )
Chest Pain, Week 49 (n=3, n=17)	1.00 ( 1.32 )	0.47 ( 1.07 )
Chest Pain, Week 50 (n=5, n=15)	0.80 ( 0.91 )	0.20 ( 0.92 )
Chest Pain, Week 51 (n=4, n=16)	0.88 ( 0.85 )	0.31 ( 0.89 )
Chest Pain, Week 52 (n=4, n=13)	0.75 ( 1.19 )	0.54 ( 1.11 )
Chest Pain, Week 53 (n=5, n=12)	0.70 ( 0.84 )	0.29 ( 1.08 )
Chest Pain, Week 54 (n=4, n=14)	1.13 ( 1.03 )	0.25 ( 0.87 )
Chest Pain, Week 55 (n=3, n=13)	1.17 ( 1.26 )	0.15 ( 0.99 )
Chest Pain, Week 56 (n=4, n=14)	0.38 ( 0.48 )	0.29 ( 0.96 )
Chest Pain, Week 57 (n=3, n=13)	0.67 ( 0.58 )	0.08 ( 0.73 )
Chest Pain, Week 58 (n=3, n=13)	1.17 ( 1.04 )	0.19 ( 1.07 )
Chest Pain, Week 59 (n=3, n=9)	1.00 ( 0.87 )	0.00 ( 0.87 )
Chest Pain, Week 60 (n=2, n=13)	0.50 ( 1.41 )	0.38 ( 1.08 )
Chest Pain, Week 61 (n=3, n=14)	1.00 ( 0.87 )	0.36 ( 1.12 )
Chest Pain, Week 62 (n=3, n=14)	0.83 ( 0.76 )	0.43 ( 1.16 )
Chest Pain, Week 63 (n=2, n=12)	0.50 ( 0.71 )	0.29 ( 0.86 )
Chest Pain, Week 64 (n=1, n=10)	0.00 ( 999999 )	0.40 ( 1.22 )
Chest Pain, Week 65 (n=1, n=13)	0.00 ( 999999 )	0.35 ( 1.11 )
Chest Pain, Week 66 (n=1, n=11)	0.00 ( 999999 )	0.45 ( 1.44 )
Chest Pain, Week 67 (n=2, n=11)	1.00 ( 1.41 )	-0.09 ( 0.80 )
Chest Pain, Week 68 (n=2, n=9)	0.75 ( 1.06 )	0.39 ( 1.45 )
Chest Pain, Week 69 (n=2, n=10)	0.50 ( 0.71 )	0.50 ( 1.33 )
Chest Pain, Week 70 (n=2, n=11)	1.00 ( 1.41 )	0.18 ( 0.81 )
Chest Pain, Week 71 (n=2, n=10)	0.50 ( 0.71 )	0.45 ( 1.32 )
Chest Pain, Week 72 (n=1, n=12)	1.00 ( 999999 )	0.42 ( 1.18 )
Chest Pain, Week 73 (n=1, n=11)	1.50 ( 999999 )	0.27 ( 1.19 )
Chest Pain, Week 74 (n=2, n=9)	0.50 ( 0.71 )	0.50 ( 1.30 )
Chest Pain, Week 75 (n=2, n=9)	0.75 ( 1.06 )	0.33 ( 1.32 )
Chest Pain, Week 76 (n=2, n=8)	0.50 ( 0.71 )	0.00 ( 0.93 )
Chest Pain, Week 77 (n=2, n=8)	0.50 ( 0.71 )	0.19 ( 1.33 )
Chest Pain, Week 78 (n=2, n=7)	1.00 ( 1.41 )	0.21 ( 1.44 )
Chest Pain, Week 79 (n=2, n=8)	0.50 ( 0.71 )	0.31 ( 1.31 )
Chest Pain, Week 80 (n=2, n=9)	0.75 ( 1.06 )	0.72 ( 1.70 )
Chest Pain, Week 81 (n=2, n=6)	0.75 ( 1.06 )	0.08 ( 1.72 )
Chest Pain, Week 82 (n=1, n=6)	0.00 ( 999999 )	0.08 ( 1.24 )
Chest Pain, Week 83 (n=1, n=6)	0.00 ( 999999 )	0.50 ( 1.48 )
Chest Pain, Week 84 (n=1, n=7)	0.50 ( 999999 )	0.43 ( 1.43 )
Chest Pain, Week 85 (n=1, n=8)	0.00 ( 999999 )	0.38 ( 1.41 )
Chest Pain, Week 86 (n=1, n=7)	0.00 ( 999999 )	0.21 ( 1.44 )
Chest Pain, Week 87 (n=1, n=7)	0.00 ( 999999 )	0.29 ( 1.41 )
Chest Pain, Week 88 (n=0, n=7)	9999 ( 9999 )	0.43 ( 1.17 )
Chest Pain, Week 89 (n=0, n=5)	9999 ( 9999 )	-0.20 ( 0.91 )
Chest Pain, Week 90 (n=0, n=7)	9999 ( 9999 )	0.07 ( 1.13 )
Chest Pain, Week 91 (n=0, n=7)	9999 ( 9999 )	-0.07 ( 0.89 )
Chest Pain, Week 92 (n=0, n=6)	9999 ( 9999 )	0.33 ( 1.54 )
Chest Pain, Week 93 (n=0, n=7)	9999 ( 9999 )	0.50 ( 1.47 )
Chest Pain, Week 94 (n=0, n=5)	9999 ( 9999 )	0.20 ( 1.35 )
Chest Pain, Week 95 (n=0, n=6)	9999 ( 9999 )	0.33 ( 1.54 )
Chest Pain, Week 96 (n=0, n=6)	9999 ( 9999 )	0.33 ( 1.54 )
Chest Pain, Week 97 (n=0, n=7)	9999 ( 9999 )	0.50 ( 1.47 )
Chest Pain, Week 98 (n=0, n=6)	9999 ( 9999 )	0.33 ( 1.54 )
Chest Pain, Week 99 (n=0, n=4)	9999 ( 9999 )	0.88 ( 1.18 )
Chest Pain, Week 100 (n=0, n=5)	9999 ( 9999 )	0.50 ( 1.00 )
Chest Pain, Week 101 (n=0, n=6)	9999 ( 9999 )	0.83 ( 0.93 )
Chest Pain, Week 102 (n=0, n=5)	9999 ( 9999 )	0.50 ( 1.00 )
Chest Pain, Week 103 (n=0, n=4)	9999 ( 9999 )	0.63 ( 1.11 )
Chest Pain, Week 104 (n=0, n=3)	9999 ( 9999 )	1.00 ( 1.00 )
Chest Pain, Week 105 (n=0, n=3)	9999 ( 9999 )	1.00 ( 1.00 )
Chest Pain, Week 106 (n=0, n=2)	9999 ( 9999 )	0.50 ( 0.71 )
Chest Pain, Week 107 (n=0, n=3)	9999 ( 9999 )	1.00 ( 1.00 )
Chest Pain, Week 108 (n=0, n=2)	9999 ( 9999 )	1.50 ( 0.71 )
Chest Pain, Week 109 (n=0, n=2)	9999 ( 9999 )	1.75 ( 1.06 )
Chest Pain, Week 110 (n=0, n=2)	9999 ( 9999 )	2.00 ( 1.41 )
Chest Pain, Week 111 (n=0, n=2)	9999 ( 9999 )	1.50 ( 0.71 )
Chest Pain, Week 112 (n=0, n=2)	9999 ( 9999 )	1.50 ( 0.71 )
Chest Pain, Week 113 (n=0, n=2)	9999 ( 9999 )	1.50 ( 0.71 )
Chest Pain, Week 114 (n=0, n=2)	9999 ( 9999 )	2.00 ( 1.41 )
Chest Pain, Week 115 (n=0, n=2)	9999 ( 9999 )	1.75 ( 1.06 )
Chest Pain, Week 116 (n=0, n=2)	9999 ( 9999 )	2.00 ( 1.41 )
Chest Pain, Week 117 (n=0, n=2)	9999 ( 9999 )	2.00 ( 1.41 )
Chest Pain, Week 118 (n=0, n=2)	9999 ( 9999 )	2.00 ( 1.41 )
Chest Pain, Week 119 (n=0, n=2)	9999 ( 9999 )	1.75 ( 1.06 )
Chest Pain, Week 120 (n=0, n=1)	9999 ( 9999 )	2.50 ( 999999 )
Chest Pain, Week 121 (n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Chest Pain, Week 122 (n=0, n=1)	9999 ( 9999 )	3.00 ( 999999 )
Chest Pain, Week 123 (n=0, n=1)	9999 ( 9999 )	2.50 ( 999999 )
Chest Pain, Week 124 (n=0, n=1)	9999 ( 9999 )	3.00 ( 999999 )
Chest Pain, Week 125 (n=0, n=1)	9999 ( 9999 )	3.00 ( 999999 )
Chest Pain, Week 126 (n=0, n=1)	9999 ( 9999 )	3.00 ( 999999 )
Chest Pain, Week 127 (n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Chest Pain, Week 128 (n=0, n=1)	9999 ( 9999 )	3.00 ( 999999 )
Chest Pain, Week 129 (n=0, n=1)	9999 ( 9999 )	3.00 ( 999999 )
Chest Pain, Week 130 (n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Chest Pain, Week 131 (n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 1 (n=44, n=47)	0.13 ( 0.86 )	0.10 ( 0.70 )
Cough, Week 2 (n=42, n=48)	-0.01 ( 0.99 )	0.19 ( 0.75 )
Cough, Week 3 (n=44, n=49)	-0.03 ( 0.76 )	-0.01 ( 0.76 )
Cough, Week 4 (n=41, n=49)	-0.02 ( 1.02 )	-0.03 ( 0.98 )
Cough, Week 5 (n=39, n=47)	-0.01 ( 0.84 )	0.00 ( 0.96 )
Cough, Week 6 (n=33, n=48)	-0.18 ( 0.93 )	-0.18 ( 0.89 )
Cough, Week 7 (n=30, n=44)	-0.20 ( 0.92 )	-0.06 ( 0.98 )
Cough, Week 8(n=29, n=44)	-0.10 ( 0.90 )	-0.13 ( 0.91 )
Cough, Week 9(n=31, n=47)	-0.24 ( 0.86 )	-0.06 ( 1.01 )
Cough, Week 10(n=30, n=40)	-0.07 ( 1.12 )	-0.10 ( 1.02 )
Cough, Week 11(n=29, n=34)	0.02 ( 1.24 )	-0.07 ( 1.07 )
Cough, Week 12(n=32, n=40)	-0.08 ( 1.30 )	-0.09 ( 0.97 )
Cough, Week 13(n=28, n=38)	-0.09 ( 1.22 )	-0.20 ( 0.93 )
Cough, Week 14(n=28, n=35)	-0.20 ( 1.19 )	-0.07 ( 0.95 )
Cough, Week 15(n=30, n=40)	-0.05 ( 1.35 )	-0.19 ( 1.04 )
Cough, Week 16(n=25, n=32)	-0.10 ( 1.06 )	-0.19 ( 0.94 )
Cough, Week 17(n=27, n=34)	-0.04 ( 0.99 )	-0.21 ( 1.09 )
Cough, Week 18(n=23, n=37)	0.02 ( 1.23 )	-0.26 ( 0.93 )
Cough, Week 19(n=22, n=32)	-0.23 ( 1.29 )	-0.27 ( 0.87 )
Cough, Week 20 (n=22, n=35)	0.00 ( 1.33 )	-0.33 ( 0.95 )
Cough, Week 21(n=18, n=36)	-0.17 ( 1.40 )	-0.19 ( 0.88 )
Cough, Week 22(n=20, n=35)	-0.20 ( 1.32 )	-0.17 ( 0.89 )
Cough, Week 23(n=16, n=33)	-0.22 ( 1.18 )	0.05 ( 0.90 )
Cough, Week 24(n=16, n=33)	-0.13 ( 1.51 )	-0.12 ( 0.80 )
Cough, Week 25(n=11, n=29)	-0.45 ( 0.96 )	0.14 ( 0.82 )
Cough, Week 26(n=13, n=32)	-0.46 ( 1.20 )	-0.03 ( 0.89 )
Cough, Week 27(n=11, n=32)	-0.50 ( 1.22 )	-0.05 ( 0.94 )
Cough, Week 28(n=11, n=30)	-0.45 ( 0.88 )	0.08 ( 0.84 )
Cough, Week 29(n=12, n=28)	-0.50 ( 1.31 )	0.05 ( 0.67 )
Cough, Week 30(n=12, n=30)	-0.88 ( 1.13 )	0.12 ( 0.88 )
Cough, Week 31(n=11, n=29)	-0.86 ( 1.40 )	0.05 ( 0.74 )
Cough, Week 32(n=11, n=23)	-0.73 ( 1.56 )	-0.04 ( 1.04 )
Cough, Week 33(n=13, n=26)	-0.77 ( 1.13 )	-0.29 ( 1.06 )
Cough, Week 34(n=10, n=26)	-0.80 ( 1.18 )	-0.02 ( 0.75 )
Cough, Week 35(n=11, n=27)	-0.14 ( 0.95 )	-0.09 ( 1.10 )
Cough, Week 36(n=9, n=25)	-0.17 ( 0.66 )	-0.36 ( 1.16 )
Cough, Week 37(n=8, n=23)	-0.25 ( 0.89 )	-0.04 ( 0.84 )
Cough, Week 38(n=11, n=21)	0.05 ( 0.88 )	-0.07 ( 1.11 )
Cough, Week 39(n=9, n=22)	-0.50 ( 0.90 )	-0.20 ( 0.97 )
Cough, Week 40(n=7, n=23)	-0.36 ( 0.94 )	-0.39 ( 1.23 )
Cough, Week 41(n=7, n=20)	0.21 ( 0.57 )	0.05 ( 0.84 )
Cough, Week 42(n=6, n=20)	0.17 ( 0.52 )	-0.20 ( 1.16 )
Cough, Week 43(n=5, n=20)	0.10 ( 0.55 )	0.03 ( 1.06 )
Cough, Week 44(n=7, n=19)	0.36 ( 0.94 )	-0.11 ( 1.09 )
Cough, Week 45(n=4, n=21)	0.25 ( 0.50 )	-0.26 ( 0.92 )
Cough, Week 46(n=5, n=19)	0.10 ( 0.96 )	0.08 ( 0.85 )
Cough, Week 47(n=4, n=18)	0.50 ( 0.58 )	-0.03 ( 0.90 )
Cough, Week 48(n=3, n=15)	0.17 ( 0.29 )	0.23 ( 0.68 )
Cough, Week 49(n=3, n=17)	0.67 ( 0.76 )	0.26 ( 0.85 )
Cough, Week 50(n=5, n=15)	0.30 ( 0.76 )	0.00 ( 0.85 )
Cough, Week 51(n=4, n=16)	0.13 ( 0.63 )	0.06 ( 0.93 )
Cough, Week 52(n=4, n=13)	0.63 ( 0.95 )	0.27 ( 0.97 )
Cough, Week 53(n=5, n=12)	0.70 ( 0.76 )	0.38 ( 0.71 )
Cough, Week 54(n=4, n=14)	0.50 ( 0.41 )	0.07 ( 0.70 )
Cough, Week 55(n=3, n=13)	0.67 ( 0.29 )	0.12 ( 0.94 )
Cough, Week 56(n=4, n=14)	0.50 ( 0.41 )	0.14 ( 0.97 )
Cough, Week 57(n=3, n=13)	0.50 ( 0.50 )	0.15 ( 0.66 )
Cough, Week 58(n=3, n=13)	0.67 ( 0.29 )	0.08 ( 1.00 )
Cough, Week 59(n=3, n=9)	0.33 ( 0.58 )	0.06 ( 0.63 )
Cough, Week 60(n=2, n=13)	0.75 ( 0.35 )	-0.04 ( 0.83 )
Cough, Week 61(n=3, n=14)	0.50 ( 0.50 )	0.00 ( 0.88 )
Cough, Week 62(n=3, n=14)	0.33 ( 0.58 )	0.14 ( 0.79 )
Cough, Week 63(n=2, n=12)	0.00 ( 0.00 )	-0.04 ( 0.86 )
Cough, Week 64(n=1, n=10)	0.00 ( 999999 )	0.35 ( 1.00 )
Cough, Week 65(n=1, n=13)	0.50 ( 999999 )	0.12 ( 0.92 )
Cough, Week 66(n=1, n=11)	0.00 ( 999999 )	0.45 ( 1.21 )
Cough, Week 67(n=2, n=11)	0.25 ( 0.35 )	-0.09 ( 0.66 )
Cough, Week 68(n=2, n=9)	0.25 ( 0.35 )	0.61 ( 1.29 )
Cough, Week 69(n=2, n=10)	0.25 ( 0.35 )	0.50 ( 1.18 )
Cough, Week 70(n=2, n=11)	0.25 ( 0.35 )	0.23 ( 0.79 )
Cough, Week 71(n=2, n=10)	0.00 ( 0.00 )	0.55 ( 0.90 )
Cough, Week 72(n=1, n=12)	-0.50 ( 999999 )	0.42 ( 0.93 )
Cough, Week 73(n=1, n=11)	0.00 ( 999999 )	0.64 ( 1.07 )
Cough, Week 74(n=2, n=9)	0.00 ( 0.00 )	0.56 ( 1.04 )
Cough, Week 75(n=2, n=9)	0.00 ( 0.71 )	0.67 ( 1.35 )
Cough, Week 76(n=2, n=8)	0.25 ( 0.35 )	0.31 ( 1.00 )
Cough, Week 77(n=2, n=8)	0.00 ( 0.00 )	0.56 ( 1.15 )
Cough, Week 78(n=2, n=7)	0.25 ( 0.35 )	0.36 ( 1.03 )
Cough, Week 79(n=2, n=8)	0.00 ( 0.00 )	0.63 ( 1.19 )
Cough, Week 80(n=2, n=9)	0.25 ( 0.35 )	0.33 ( 0.90 )
Cough, Week 81(n=2, n=6)	0.25 ( 0.35 )	0.58 ( 1.28 )
Cough, Week 82(n=1, n=6)	0.00 ( 999999 )	0.25 ( 1.08 )
Cough, Week 83(n=1, n=6)	0.00 ( 999999 )	0.67 ( 1.21 )
Cough, Week 84(n=1, n=7)	0.50 ( 999999 )	0.29 ( 0.95 )
Cough, Week 85(n=1, n=8)	0.00 ( 999999 )	0.38 ( 1.03 )
Cough, Week 86(n=1, n=7)	0.00 ( 999999 )	0.57 ( 1.24 )
Cough, Week 87(n=1, n=7)	0.00 ( 999999 )	0.64 ( 1.35 )
Cough, Week 88(n=0, n=7)	9999 ( 9999 )	0.64 ( 1.14 )
Cough, Week 89 (n=0, n=5)	9999 ( 9999 )	0.50 ( 1.32 )
Cough, Week 90(n=0, n=7)	9999 ( 9999 )	0.43 ( 1.10 )
Cough, Week 91(n=0, n=7)	9999 ( 9999 )	0.50 ( 1.19 )
Cough, Week 92(n=0, n=6)	9999 ( 9999 )	0.67 ( 1.21 )
Cough, Week 93(n=0, n=7)	9999 ( 9999 )	0.79 ( 1.38 )
Cough, Week 94(n=0, n=5)	9999 ( 9999 )	0.30 ( 0.97 )
Cough, Week 95(n=0, n=6)	9999 ( 9999 )	0.67 ( 1.25 )
Cough, Week 96(n=0, n=6)	9999 ( 9999 )	0.58 ( 1.20 )
Cough, Week 97(n=0, n=7)	9999 ( 9999 )	0.57 ( 1.13 )
Cough, Week 98(n=0, n=6)	9999 ( 9999 )	0.67 ( 1.25 )
Cough, Week 99(n=0, n=4)	9999 ( 9999 )	0.25 ( 0.96 )
Cough, Week 100(n=0, n=5)	9999 ( 9999 )	0.60 ( 1.14 )
Cough, Week 101(n=0, n=6)	9999 ( 9999 )	0.50 ( 1.05 )
Cough, Week 102(n=0, n=5)	9999 ( 9999 )	0.50 ( 1.00 )
Cough, Week 103(n=0, n=4)	9999 ( 9999 )	0.25 ( 0.96 )
Cough, Week 104(n=0, n=3)	9999 ( 9999 )	0.00 ( 1.00 )
Cough, Week 105(n=0, n=3)	9999 ( 9999 )	0.33 ( 1.53 )
Cough, Week 106(n=0, n=2)	9999 ( 9999 )	-0.50 ( 0.71 )
Cough, Week 107(n=0, n=3)	9999 ( 9999 )	0.00 ( 1.00 )
Cough, Week 108(n=0, n=2)	9999 ( 9999 )	0.00 ( 1.41 )
Cough, Week 109(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 110(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 111(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 112(n=0, n=2)	9999 ( 9999 )	0.00 ( 1.41 )
Cough, Week 113(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 114(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 115(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 116(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 117(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 118(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 119(n=0, n=2)	9999 ( 9999 )	0.50 ( 2.12 )
Cough, Week 120(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 121(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 122(n=0, n=)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 123(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 124(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 125(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 126(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 127(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 128(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 129(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 130(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Cough, Week 131(n=0, n=1)	9999 ( 9999 )	2.00 ( 999999 )
Dyspnoea, Week 1(n=44, n=47)	0.42 ( 0.81 )	0.12 ( 0.76 )
Dyspnoea, Week 2(n=42, n=48)	0.33 ( 0.73 )	0.29 ( 0.87 )
Dyspnoea, Week 3(n=44, n=49)	0.25 ( 0.75 )	0.25 ( 0.97 )
Dyspnoea, Week 4(n=41, n=49)	0.43 ( 0.87 )	0.28 ( 0.89 )
Dyspnoea, Week 5(n=39, n=47)	0.55 ( 0.81 )	0.21 ( 1.00 )
Dyspnoea, Week 6(n=33, n=48)	0.50 ( 0.68 )	0.21 ( 0.95 )
Dyspnoea, Week 7(n=30, n=44)	0.63 ( 0.74 )	0.32 ( 1.08 )
Dyspnoea, Week 8(n=29, n=44)	0.50 ( 0.64 )	0.25 ( 1.00 )
Dyspnoea, Week 9(n=31, n=47)	0.46 ( 0.86 )	0.34 ( 1.01 )
Dyspnoea, Week 10(n=30, n=40)	0.43 ( 0.80 )	0.49 ( 1.12 )
Dyspnoea, Week 11 (n=29, n=34)	0.36 ( 0.77 )	0.24 ( 0.97 )
Dyspnoea, Week 12 (n=32, n=40)	0.39 ( 0.82 )	0.35 ( 1.04 )
Dyspnoea, Week 13 (n=28, n=38)	0.43 ( 0.83 )	0.23 ( 0.94 )
Dyspnoea, Week 14 (n=28, n=35)	0.26 ( 0.88 )	0.26 ( 1.14 )
Dyspnoea, Week 15 (n=30, n=40)	0.36 ( 1.07 )	0.39 ( 1.22 )
Dyspnoea, Week 16 (n=25, n=32)	0.18 ( 0.82 )	0.26 ( 1.13 )
Dyspnoea, Week 17 (n=27, n=34)	0.48 ( 0.87 )	0.16 ( 1.17 )
Dyspnoea, Week 18 (n=23, n=37)	0.39 ( 0.65 )	0.21 ( 1.05 )
Dyspnoea, Week 19 (n=22, n=32)	0.29 ( 0.86 )	0.33 ( 1.12 )
Dyspnoea, Week 20 (n=22, n=35)	0.60 ( 0.87 )	0.23 ( 1.00 )
Dyspnoea, Week 21 (n=18, n=36)	0.27 ( 0.69 )	0.40 ( 0.93 )
Dyspnoea, Week 22 (n=20, n=35)	0.55 ( 0.92 )	0.22 ( 0.99 )
Dyspnoea, Week 23 (n=16, n=33)	0.34 ( 0.69 )	0.38 ( 0.98 )
Dyspnoea, Week 24 (n=16, n=33)	0.36 ( 1.02 )	0.42 ( 1.06 )
Dyspnoea, Week 25 (n=11, n=29)	0.22 ( 0.46 )	0.50 ( 1.14 )
Dyspnoea, Week 26 (n=13, n=32)	0.32 ( 0.82 )	0.28 ( 0.95 )
Dyspnoea, Week 27 (n=11, n=32)	0.35 ( 1.07 )	0.37 ( 1.04 )
Dyspnoea, Week 28 (n=11, n=30)	0.35 ( 0.92 )	0.45 ( 0.83 )
Dyspnoea, Week 29 (n=12, n=28)	0.20 ( 0.89 )	0.38 ( 0.85 )
Dyspnoea, Week 30 (n=12, n=30)	0.18 ( 0.96 )	0.54 ( 1.01 )
Dyspnoea, Week 31 (n=11, n=29)	0.18 ( 0.84 )	0.41 ( 0.86 )
Dyspnoea, Week 32 (n=11, n=23)	0.22 ( 1.00 )	0.58 ( 1.04 )
Dyspnoea, Week 33 (n=13, n=26)	0.20 ( 0.78 )	0.36 ( 0.96 )
Dyspnoea, Week 34 (n=10, n=26)	0.16 ( 0.79 )	0.28 ( 1.00 )
Dyspnoea, Week 35 (n=11, n=27)	0.11 ( 0.58 )	0.27 ( 1.02 )
Dyspnoea, Week 36 (n=9, n=25)	0.11 ( 0.86 )	-0.02 ( 1.04 )
Dyspnoea, Week 37 (n=8, n=23)	0.28 ( 0.63 )	0.42 ( 1.13 )
Dyspnoea, Week 38 (n=11, n=21)	0.40 ( 0.76 )	0.50 ( 1.25 )
Dyspnoea, Week 39 (n=9, n=22)	0.27 ( 0.81 )	0.25 ( 0.86 )
Dyspnoea, Week 40 (n=7, n=23)	0.57 ( 0.76 )	0.44 ( 1.13 )
Dyspnoea, Week 41 (n=7, n=20)	0.31 ( 0.58 )	0.53 ( 1.17 )
Dyspnoea, Week 42 (n=6, n=20)	0.30 ( 0.55 )	0.52 ( 1.07 )
Dyspnoea, Week 43 (n=5, n=20)	0.40 ( 0.57 )	0.41 ( 1.18 )
Dyspnoea, Week 44 (n=7, n=19)	0.49 ( 0.60 )	0.31 ( 1.14 )
Dyspnoea, Week 45 (n=4, n=21)	0.65 ( 0.38 )	0.53 ( 1.04 )
Dyspnoea, Week 46 (n=5, n=19)	0.56 ( 0.71 )	0.37 ( 0.97 )
Dyspnoea, Week 47 (n=4, n=18)	0.30 ( 0.68 )	0.39 ( 0.92 )
Dyspnoea, Week 48 (n=3, n=15)	0.60 ( 0.72 )	0.39 ( 0.93 )
Dyspnoea, Week 49 (n=3, n=17)	1.40 ( 1.20 )	0.47 ( 0.76 )
Dyspnoea, Week 50 (n=5, n=15)	0.24 ( 0.59 )	0.53 ( 0.96 )
Dyspnoea, Week 51 (n=4, n=16)	1.05 ( 1.02 )	0.59 ( 1.02 )
Dyspnoea, Week 52 (n=4, n=13)	1.10 ( 1.01 )	0.72 ( 1.20 )
Dyspnoea, Week 53 (n=5, n=12)	0.76 ( 1.28 )	0.40 ( 1.01 )
Dyspnoea, Week 54 (n=4, n=14)	1.10 ( 1.16 )	0.63 ( 1.02 )
Dyspnoea, Week 55 (n=3, n=13)	1.00 ( 0.53 )	0.72 ( 1.13 )
Dyspnoea, Week 56 (n=4, n=14)	0.40 ( 0.86 )	0.61 ( 1.07 )
Dyspnoea, Week 57 (n=3, n=13)	0.53 ( 0.61 )	0.45 ( 1.02 )
Dyspnoea, Week 58 (n=3, n=13)	0.80 ( 0.53 )	0.60 ( 1.20 )
Dyspnoea, Week 59 (n=3, n=9)	0.60 ( 0.72 )	0.18 ( 1.08 )
Dyspnoea, Week 60 (n=2, n=13)	1.20 ( 1.13 )	0.57 ( 0.89 )
Dyspnoea, Week 61 (n=3, n=14)	0.73 ( 0.76 )	0.54 ( 1.00 )
Dyspnoea, Week 62 (n=3, n=14)	0.67 ( 0.83 )	0.66 ( 1.11 )
Dyspnoea, Week 63 (n=2, n=12)	0.30 ( 0.42 )	0.77 ( 0.80 )
Dyspnoea, Week 64 (n=1, n=10)	0.20 ( 999999 )	0.66 ( 1.07 )
Dyspnoea, Week 65 (n=1, n=13)	0.60 ( 999999 )	0.94 ( 1.28 )
Dyspnoea, Week 66 (n=1, n=11)	0.40 ( 999999 )	0.67 ( 1.31 )
Dyspnoea, Week 67 (n=2, n=11)	0.50 ( 0.14 )	0.33 ( 0.87 )
Dyspnoea, Week 68 (n=2, n=9)	0.20 ( 0.28 )	0.82 ( 1.56 )
Dyspnoea, Week 69 (n=2, n=10)	0.30 ( 0.42 )	0.74 ( 1.11 )
Dyspnoea, Week 70 (n=2, n=11)	0.30 ( 0.42 )	0.75 ( 1.16 )
Dyspnoea, Week 71 (n=2, n=10)	0.10 ( 0.14 )	0.84 ( 1.19 )
Dyspnoea, Week 72 (n=1, n=12)	0.00 ( 999999 )	0.80 ( 1.09 )
Dyspnoea, Week 73 (n=1, n=11)	0.00 ( 999999 )	0.67 ( 1.11 )
Dyspnoea, Week 74 (n=2, n=9)	0.20 ( 0.28 )	0.89 ( 1.35 )
Dyspnoea, Week 75 (n=2, n=9)	0.30 ( 0.42 )	0.71 ( 1.31 )
Dyspnoea, Week 76 (n=1, n=8)	0.30 ( 0.42 )	0.53 ( 1.05 )
Dyspnoea, Week 77 (n=2, n=8)	0.40 ( 0.57 )	0.65 ( 1.55 )
Dyspnoea, Week 78 (n=2, n=7)	0.30 ( 0.14 )	0.40 ( 1.11 )
Dyspnoea, Week 79 (n=2, n=8)	0.10 ( 0.14 )	0.55 ( 1.25 )
Dyspnoea, Week 80 (n=2, n=9)	0.50 ( 0.71 )	0.69 ( 1.43 )
Dyspnoea, Week 81 (n=2, n=6)	0.40 ( 0.57 )	0.53 ( 1.53 )
Dyspnoea, Week 82 (n=1, n=6)	0.60 ( 999999 )	0.53 ( 1.09 )
Dyspnoea, Week 83 (n=1, n=6)	0.60 ( 999999 )	0.87 ( 1.28 )
Dyspnoea, Week 84 (n=1, n=7)	0.80 ( 999999 )	0.89 ( 1.13 )
Dyspnoea, Week 85 (n=1, n=8)	0.60 ( 999999 )	0.83 ( 1.27 )
Dyspnoea, Week 86 (n=1, n=7)	0.40 ( 999999 )	0.66 ( 1.33 )
Dyspnoea, Week 87 (n=1, n=7)	0.40 ( 999999 )	0.66 ( 1.23 )
Dyspnoea, Week 88 (n=0, n=7)	9999 ( 9999 )	1.20 ( 1.43 )
Dyspnoea, Week 89 (n=5, n=5)	9999 ( 9999 )	0.56 ( 1.05 )
Dyspnoea, Week 90 (n=0, n=7)	9999 ( 9999 )	0.74 ( 1.38 )
Dyspnoea, Week 91 (n=0, n=7)	9999 ( 9999 )	0.51 ( 1.00 )
Dyspnoea, Week 92 (n=0, n=6)	9999 ( 9999 )	0.87 ( 1.26 )
Dyspnoea, Week 93 (n=0, n=7)	9999 ( 9999 )	1.20 ( 1.39 )
Dyspnoea, Week 94 (n=0, n=5)	9999 ( 9999 )	0.48 ( 0.99 )
Dyspnoea, Week 95 (n=0, n=6)	9999 ( 9999 )	0.87 ( 1.32 )
Dyspnoea, Week 96 (n=0, n=6)	9999 ( 9999 )	1.13 ( 1.24 )
Dyspnoea, Week 97 (n=0, n=7)	9999 ( 9999 )	1.26 ( 1.35 )
Dyspnoea, Week 98 (n=0, n=6)	9999 ( 9999 )	0.80 ( 1.19 )
Dyspnoea, Week 99 (n=0, n=4)	9999 ( 9999 )	0.70 ( 1.58 )
Dyspnoea, Week 100 (n=0, n=5)	9999 ( 9999 )	0.88 ( 1.38 )
Dyspnoea, Week 101 (n=0, n=6)	9999 ( 9999 )	1.13 ( 1.54 )
Dyspnoea, Week 102 (n=0, n=5)	9999 ( 9999 )	0.96 ( 1.58 )
Dyspnoea, Week 103 (n=0, n=4)	9999 ( 9999 )	0.55 ( 1.68 )
Dyspnoea, Week 104 (n=0, n=3)	9999 ( 9999 )	1.07 ( 1.33 )
Dyspnoea, Week 105 (n=0, n=3)	9999 ( 9999 )	1.07 ( 1.33 )
Dyspnoea, Week 106 (n=0, n=2)	9999 ( 9999 )	0.40 ( 0.28 )
Dyspnoea, Week 107 (n=0, n=3)	9999 ( 9999 )	1.13 ( 1.63 )
Dyspnoea, Week 108 (n=0, n=2)	9999 ( 9999 )	1.50 ( 1.56 )
Dyspnoea, Week 109 (n=0, n=2)	9999 ( 9999 )	1.30 ( 1.27 )
Dyspnoea, Week 110 (n=0, n=2)	9999 ( 9999 )	1.50 ( 1.56 )
Dyspnoea, Week 111 (n=0, n=2)	9999 ( 9999 )	1.60 ( 1.41 )
Dyspnoea, Week 112 (n=0, n=2)	9999 ( 9999 )	1.50 ( 1.56 )
Dyspnoea, Week 113 (n=0, n=2)	9999 ( 9999 )	1.50 ( 1.56 )
Dyspnoea, Week 114 (n=0, n=2)	9999 ( 9999 )	1.60 ( 1.70 )
Dyspnoea, Week 115 (n=0, n=2)	9999 ( 9999 )	1.40 ( 1.41 )
Dyspnoea, Week 116 (n=0, n=2)	9999 ( 9999 )	1.30 ( 1.27 )
Dyspnoea, Week 117 (n=0, n=2)	9999 ( 9999 )	1.50 ( 1.56 )
Dyspnoea, Week 118 (n=0, n=2)	9999 ( 9999 )	1.30 ( 1.27 )
Dyspnoea, Week 119 (n=0, n=2)	9999 ( 9999 )	1.50 ( 1.56 )
Dyspnoea, Week 120 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 121 (n=0, n=1)	9999 ( 9999 )	2.40 ( 999999 )
Dyspnoea, Week 122 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 123 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 124 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 125 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 126 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 127 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 128 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 129 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 130 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )
Dyspnoea, Week 131 (n=0, n=1)	9999 ( 9999 )	2.20 ( 999999 )

No statistical analyses for this end point

Secondary: TTD as Assessed Using EORTC QLQ Supplementary Lung Cancer Module (EORTC QLQ-LC13) in the TC3 or IC3-WT Populations

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End point title

TTD as Assessed Using EORTC QLQ Supplementary Lung Cancer Module (EORTC QLQ-LC13) in the TC3 or IC3-WT Populations

End point description

TTD in patient-reported lung cancer symptoms, defined as time from randomization to deterioration (10-point change) in any of the following symptom subscales (cough, dyspnea [multi-item scale], and chest pain), whichever occurs first, as measured by the EORTC QLQ-LC13. EORTC QLQ-LC13 module incorporates one multi-item scale to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Note: 999999=not estimable.

End point type

Secondary

End point timeframe

Baseline until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	98	107
Units: Months
median (confidence interval 95%)
Cough (n=98, n=107)	999999 (999999 to 999999)	999999 (21.5 to 999999)
Dyspnea(n=98, n=107)	11.8 (6.8 to 19.5)	11.1 (7.0 to 999999)
Chest pain(n=98, n=107)	999999 (999999 to 999999)	999999 (999999 to 999999)

TTD Using EORTC QLQ-LC13 Statistical Analysis

Statistical analysis description

Cough for TC3 or IC3-WT Populations

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.984

Confidence interval

level

95%

sides

2-sided

lower limit

0.477

upper limit

2.03

Notes
[20] - Stratified analysis

TTD Using EORTC QLQ-LC13 Statistical Analysis

Statistical analysis description

Chest pain for TC3 or IC3-WT Populations

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.024

Confidence interval

level

95%

sides

2-sided

lower limit

0.472

upper limit

2.222

Notes
[21] - Stratified analysis

TTD Using EORTC QLQ-LC13 Statistical Analysis

Statistical analysis description

Dyspnea for TC3 or IC3-WT Populations

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.955

Confidence interval

level

95%

sides

2-sided

lower limit

0.569

upper limit

1.604

Notes
[22] - Stratified analysis

Secondary: OS in Participants with PD-L1 Expression

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End point title

OS in Participants with PD-L1 Expression

End point description

OS is defined as the time from randomization to death from any cause. Note: 999999=not estimable.

End point type

Secondary

End point timeframe

From randomization to death from any cause until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	210	212
Units: Months
median (confidence interval 95%)
SP263 >=50%-WT Population (n=143, n=150)	16.1 (9.8 to 17.4)	19.5 (13.8 to 999999)
SP263 >=25%-WT Population (n=168, n=168)	12.6 (9.1 to 17.0)	18.2 (13.3 to 999999)
SP263 =1%-WT Population(n=210, n=212)	14.0 (9.8 to 16.5)	17.8 (12.8 to 23.1)

OS in Participants With PD-L1 Statistical Analysis

Statistical analysis description

SP263 >=50%-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

422

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.707

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

Notes
[23] - Unstratified analysis

OS in Participants With PD-L1 Statistical Analysis

Statistical analysis description

SP263 >=1%-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

422

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.768

Confidence interval

level

95%

sides

2-sided

lower limit

0.579

upper limit

1.018

Notes
[24] - Unstratified analysis

OS in Participants With PD-L1 Statistical Analysis

Statistical analysis description

SP263 >=25%-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

422

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.693

Confidence interval

level

95%

sides

2-sided

lower limit

0.502

upper limit

0.956

Notes
[25] - Unstratified analysis

Secondary: Investigator-Assessed PFS in Participants with PD-L1 Expression According to RECIST v1.1

Top of page

End point title

Investigator-Assessed PFS in Participants with PD-L1 Expression According to RECIST v1.1

End point description

Investigator-assessed PFS according to RECIST v1.1 in the PD-L1 (defined with SP263 IHC assay)

End point type

Secondary

End point timeframe

From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	210	212
Units: Months
median (confidence interval 95%)
SP263 >=50%-WT Population (n=143, n=150)	4.9 (4.0 to 5.6)	7.0 (5.6 to 8.7)
SP263 >=25%-WT Population(n=168, n=168)	4.9 (4.2 to 5.6)	6.9 (5.6 to 8.4)
SP263 >=1%-WT Population(n=210, n=212)	5.4 (4.4 to 5.7)	6.8 (5.5 to 8.0)

Investigator-Assessed PFS Statistical Analysis

Statistical analysis description

SP263 >=50%-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

422

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.674

Confidence interval

level

95%

sides

2-sided

lower limit

0.511

upper limit

0.89

Notes
[26] - Unstratified analysis

Investigator-Assessed PFS Statistical Analysis

Statistical analysis description

SP263 >=1%-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

422

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.725

Confidence interval

level

95%

sides

2-sided

lower limit

0.577

upper limit

0.91

Notes
[27] - Unstratified analysis

Investigator-Assessed PFS Statistical Analysis

Statistical analysis description

SP263 >=25%-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

422

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.698

Confidence interval

level

95%

sides

2-sided

lower limit

0.539

upper limit

0.904

Notes
[28] - Unstratified analysis

Secondary: OS in Participants with Blood Tumor Mutational Burden (bTMB)

Top of page

End point title

OS in Participants with Blood Tumor Mutational Burden (bTMB)

End point description

OS is defined as the time from randomization to death from any cause. Note: 999999=not estimable.

End point type

Secondary

End point timeframe

From randomization to death from any cause until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	83	92
Units: Months
median (confidence interval 95%)
bTMB >=10-WT Population (n=83, n=92)	10.3 (7.1 to 16.9)	11.2 (7.9 to 999999)
bTMB >=16-WT Population(n=45, n=42)	8.5 (5.8 to 999999)	13.9 (10.8 to 999999)
bTMB >=20-WT Population(n=29, n=27)	10.5 (5.8 to 999999)	17.2 (10.8 to 999999)

OS in Participants with bTMB

Statistical analysis description

bTMB >=10-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.867

Confidence interval

level

95%

sides

2-sided

lower limit

0.578

upper limit

1.301

Notes
[29] - Unstratified analysis

OS in Participants with bTMB

Statistical analysis description

bTMB >=20-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.362

upper limit

1.638

Notes
[30] - Unstratified analysis

OS in Participants with bTMB

Statistical analysis description

bTMB >=16-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.748

Confidence interval

level

95%

sides

2-sided

lower limit

0.414

upper limit

1.351

Notes
[31] - Unstratified analysis

Secondary: Investigator-Assessed PFS in Participants with bTMB According to RECIST v1.1

Top of page

End point title

Investigator-Assessed PFS in Participants with bTMB According to RECIST v1.1

End point description

PFS according to RECIST v1.1 in the bTMB subpopulations.

End point type

Secondary

End point timeframe

From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months)

End point values	Chemotherapy	Atezolizumab
Number of subjects analysed	83	92
Units: Months
median (confidence interval 95%)
bTMB >=10-WT Population (n=83, n=92)	4.3 (3.1 to 5.4)	5.5 (2.8 to 6.8)
bTMB >=16-WT Population(n=45, n=42)	4.4 (2.8 to 5.7)	6.8 (4.3 to 11.6)
bTMB >=20-WT Population(n=29, n=27)	5.2 (3.2 to 6.4)	6.8 (4.3 to 17.2)

Investigator-Assessed PFS Statistical Analysis

Statistical analysis description

bTMB >=10-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.743

Confidence interval

level

95%

sides

2-sided

lower limit

0.525

upper limit

1.052

Notes
[32] - Unstratified analysis

Investigator-Assessed PFS Statistical Analysis

Statistical analysis description

bTMB >=20-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.295

upper limit

1.062

Notes
[33] - Unstratified analysis

Investigator-Assessed PFS Statistical Analysis

Statistical analysis description

bTMB >=16-WT Population

Comparison groups

Chemotherapy v Atezolizumab

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.553

Confidence interval

level

95%

sides

2-sided

lower limit

0.331

upper limit

0.924

Notes
[34] - Unstratified analysis

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab

Top of page

End point title

Minimum Observed Serum Concentration (Cmin) of Atezolizumab ^[35]

End point description

Note: 999999=not estimable.

End point type

Secondary

End point timeframe

Prior to infusion (0 hour) on Day 1 of Cycles 2, 3, 4, 8, 16, and every eighth cycle thereafter, and at treatment discontinuation until data cut-off on 10 September 2018 (up to approximately 38 months) (cycle duration = 21 days)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Atezolizumab
Number of subjects analysed	256
Units: micrograms per milliliter (μg/ mL)
arithmetic mean (standard deviation)
Cycle 2 Day 1 (n=256)	76.7 ( 57.6 )
Cycle 3 Day 1 (n=215)	121 ( 57.7 )
Cycle 4 Day 1 (n=207)	154 ( 90.1 )
Cycle 8 Day 1 (n=145)	201 ( 98.6 )
Cycle 16 Day 1 (n=67)	213 ( 102 )
Cycle 24 Day 1 (n=31)	245 ( 128 )
Cycle 32 Day 1 (n=10)	276 ( 110 )
Cycle 40 Day 1 (n=5)	252 ( 160 )
Cycle 48 Day 1 (n=1)	555 ( 999999 )
Treatment Discontinuation Visit (n=100)	121 ( 88.8 )

No statistical analyses for this end point

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab

Top of page

End point title

Maximum Observed Serum Concentration (Cmax) of Atezolizumab ^[36]

End point description

End point type

Secondary

End point timeframe

0 hour (predose) and 30 minutes after atezolizumab infusion on Day 1 (infusion duration = up to 1 hour)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Atezolizumab
Number of subjects analysed	270
Units: micrograms per milliliter (μg/ mL)
arithmetic mean (standard deviation)	411 ( 163 )

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Adverse Event

Top of page

End point title

Percentage of Participants With at Least One Adverse Event

End point description

Percentage of participants with at least one adverse event in the Safety Population. Safety analyses included treated participants, defined as randomized participants who received any amount of study treatment.

End point type

Secondary

End point timeframe

Baseline up to until data cut-off on 8 March 2022 (up to approximately 79.5 months)

End point values	Chemotherapy Safety Population	Atezolizumab Safety Population
Number of subjects analysed	263	286
Units: Percentage of participants
number (not applicable)	95.1	92.3

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-therapeutic Antibodies (ATAs)

Top of page

End point title

Percentage of Participants With Anti-therapeutic Antibodies (ATAs) ^[37]

End point description

End point type

Secondary

End point timeframe

Baseline until data cut-off on 10 September 2018 (up to approximately 38 months)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Atezolizumab
Number of subjects analysed	282
Units: Percentage of participants
number (not applicable)
Baseline evaluable participants (n=282)	1.4
Post-baseline evaluable participants (n=267)	24.3

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the first study drug until the data cut-off on 8 March 2022 (up to approximately 79.5 months).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Atezolizumab

Reporting group description

Reporting group title

Chemotherapy

Reporting group description

Serious adverse events	Atezolizumab	Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	97 / 286 (33.92%)	77 / 263 (29.28%)
number of deaths (all causes)	213	212
number of deaths resulting from adverse events	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Transitional cell carcinoma
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary neoplasm
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal cancer
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic neoplasm
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Langerhans' cell histiocytosis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Thrombophlebitis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic aneurysm rupture
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Varicose vein
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vein disorder
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Cataract operation
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Swelling
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	4 / 286 (1.40%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	3 / 286 (1.05%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 286 (0.70%)	3 / 263 (1.14%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 3
Asthenia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Immune system disorder
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	2 / 286 (0.70%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 286 (0.00%)	4 / 263 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 286 (0.70%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	8 / 286 (2.80%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 14	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Aspiration
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 286 (0.00%)	2 / 263 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonitis
subjects affected / exposed	6 / 286 (2.10%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	10 / 10	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	6 / 286 (2.10%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 6	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchial obstruction
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Thrombosis in device
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	2 / 286 (0.70%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation pneumonitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	2 / 286 (0.70%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune myocarditis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 286 (0.35%)	2 / 263 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Cardiac failure
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Myocardial ischaemia
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral ischaemia
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid arteriosclerosis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Seizure
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurological decompensation
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 286 (0.00%)	5 / 263 (1.90%)
occurrences causally related to treatment / all	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 286 (0.00%)	5 / 263 (1.90%)
occurrences causally related to treatment / all	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 286 (0.00%)	3 / 263 (1.14%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Thrombocytopenia
subjects affected / exposed	1 / 286 (0.35%)	9 / 263 (3.42%)
occurrences causally related to treatment / all	1 / 1	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytosis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 286 (0.35%)	10 / 263 (3.80%)
occurrences causally related to treatment / all	0 / 1	14 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal motility disorder
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 286 (0.00%)	2 / 263 (0.76%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune colitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nausea
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	2 / 286 (0.70%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune dermatitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute febrile neutrophilic dermatosis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal impairment
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ketonuria
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Glucocorticoid deficiency
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pathological fracture
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fistula
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess neck
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural infection
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	15 / 286 (5.24%)	14 / 263 (5.32%)
occurrences causally related to treatment / all	0 / 25	3 / 14
deaths causally related to treatment / all	0 / 1	0 / 1
Mycotic endophthalmitis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle abscess
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	3 / 286 (1.05%)	3 / 263 (1.14%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Infectious pleural effusion
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 286 (0.70%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	1 / 286 (0.35%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periodontitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	3 / 286 (1.05%)	4 / 263 (1.52%)
occurrences causally related to treatment / all	0 / 3	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Sepsis
subjects affected / exposed	2 / 286 (0.70%)	2 / 263 (0.76%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Upper respiratory tract infection
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 286 (0.70%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial colitis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	2 / 286 (0.70%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post-acute COVID-19 syndrome
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Tumour lysis syndrome
subjects affected / exposed	0 / 286 (0.00%)	1 / 263 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	3 / 286 (1.05%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	3 / 286 (1.05%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 286 (0.00%)	2 / 263 (0.76%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 286 (0.35%)	0 / 263 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Atezolizumab	Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	238 / 286 (83.22%)	230 / 263 (87.45%)
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	29 / 286 (10.14%)	11 / 263 (4.18%)
occurrences all number	35	12
Blood creatinine increased
subjects affected / exposed	9 / 286 (3.15%)	27 / 263 (10.27%)
occurrences all number	12	33
Alanine aminotransferase increased
subjects affected / exposed	30 / 286 (10.49%)	16 / 263 (6.08%)
occurrences all number	34	17
Neutrophil count decreased
subjects affected / exposed	0 / 286 (0.00%)	19 / 263 (7.22%)
occurrences all number	0	27
White blood cell count decreased
subjects affected / exposed	3 / 286 (1.05%)	14 / 263 (5.32%)
occurrences all number	17	24
Weight decreased
subjects affected / exposed	25 / 286 (8.74%)	15 / 263 (5.70%)
occurrences all number	27	15
Platelet count decreased
subjects affected / exposed	1 / 286 (0.35%)	21 / 263 (7.98%)
occurrences all number	1	30
Nervous system disorders
Headache
subjects affected / exposed	31 / 286 (10.84%)	18 / 263 (6.84%)
occurrences all number	32	20
Dizziness
subjects affected / exposed	9 / 286 (3.15%)	14 / 263 (5.32%)
occurrences all number	9	18
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	4 / 286 (1.40%)	21 / 263 (7.98%)
occurrences all number	6	31
Anaemia
subjects affected / exposed	50 / 286 (17.48%)	120 / 263 (45.63%)
occurrences all number	73	153
Thrombocytopenia
subjects affected / exposed	8 / 286 (2.80%)	40 / 263 (15.21%)
occurrences all number	8	62
Neutropenia
subjects affected / exposed	5 / 286 (1.75%)	71 / 263 (27.00%)
occurrences all number	7	128
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	40 / 286 (13.99%)	25 / 263 (9.51%)
occurrences all number	58	30
Fatigue
subjects affected / exposed	44 / 286 (15.38%)	47 / 263 (17.87%)
occurrences all number	47	57
Chest pain
subjects affected / exposed	21 / 286 (7.34%)	10 / 263 (3.80%)
occurrences all number	28	10
Asthenia
subjects affected / exposed	41 / 286 (14.34%)	47 / 263 (17.87%)
occurrences all number	58	66
Oedema peripheral
subjects affected / exposed	13 / 286 (4.55%)	16 / 263 (6.08%)
occurrences all number	14	18
Gastrointestinal disorders
Nausea
subjects affected / exposed	42 / 286 (14.69%)	88 / 263 (33.46%)
occurrences all number	49	148
Diarrhoea
subjects affected / exposed	39 / 286 (13.64%)	30 / 263 (11.41%)
occurrences all number	55	39
Constipation
subjects affected / exposed	42 / 286 (14.69%)	58 / 263 (22.05%)
occurrences all number	48	75
Vomiting
subjects affected / exposed	21 / 286 (7.34%)	34 / 263 (12.93%)
occurrences all number	27	45
Stomatitis
subjects affected / exposed	12 / 286 (4.20%)	14 / 263 (5.32%)
occurrences all number	14	16
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	36 / 286 (12.59%)	25 / 263 (9.51%)
occurrences all number	48	27
Dyspnoea
subjects affected / exposed	41 / 286 (14.34%)	26 / 263 (9.89%)
occurrences all number	48	32
Haemoptysis
subjects affected / exposed	23 / 286 (8.04%)	9 / 263 (3.42%)
occurrences all number	25	12
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	23 / 286 (8.04%)	8 / 263 (3.04%)
occurrences all number	26	8
Pruritus
subjects affected / exposed	25 / 286 (8.74%)	4 / 263 (1.52%)
occurrences all number	33	4
Alopecia
subjects affected / exposed	3 / 286 (1.05%)	16 / 263 (6.08%)
occurrences all number	3	16
Psychiatric disorders
Insomnia
subjects affected / exposed	22 / 286 (7.69%)	15 / 263 (5.70%)
occurrences all number	25	16
Endocrine disorders
Hypothyroidism
subjects affected / exposed	27 / 286 (9.44%)	3 / 263 (1.14%)
occurrences all number	28	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	31 / 286 (10.84%)	8 / 263 (3.04%)
occurrences all number	46	8
Back pain
subjects affected / exposed	26 / 286 (9.09%)	14 / 263 (5.32%)
occurrences all number	28	15
Infections and infestations
Nasopharyngitis
subjects affected / exposed	22 / 286 (7.69%)	7 / 263 (2.66%)
occurrences all number	37	8
Pneumonia
subjects affected / exposed	15 / 286 (5.24%)	8 / 263 (3.04%)
occurrences all number	17	8
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	19 / 286 (6.64%)	12 / 263 (4.56%)
occurrences all number	29	19
Decreased appetite
subjects affected / exposed	50 / 286 (17.48%)	50 / 263 (19.01%)
occurrences all number	65	61
Hyperglycaemia
subjects affected / exposed	12 / 286 (4.20%)	15 / 263 (5.70%)
occurrences all number	18	17

More information

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Were there any global substantial amendments to the protocol? Yes

05 Oct 2015

Protocol was amended to include modification of inclusion criteria to allow for patients with treated, asymptomatic cerebellar metastases to be enrolled provided specific criteria were met. The exclusion criteria for history of autoimmune disease was broadened to allow for patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only to be permitted provided that they met the specific conditions. The exclusion criterion specifying that patients with a history of allergic reaction to IV contrast that requires steroid pretreatment should have baseline and subsequent tumor assessments performed via MRI was removed.

16 Dec 2015

Protocol was amended to include clarification that a wash-out period of at least 4 weeks or five half-lives, whichever was longer, of any systemic immunostimulatory agent was required prior to randomization.

29 Jun 2016

Protocol was amended to expand the patient population to include patients with squamous NSCLC, who was randomized to receive either atezolizumab or chemotherapy consisting of a platinum agent (carboplatin or cisplatin per investigator discretion) combined with gemcitabine (in contrast to patients with non-squamous NSCLC, who received either atezolizumab or chemotherapy consisting of a platinum agent combined with pemetrexed). Cuff-off revised for PD-L1 expression in TCs and ICs to allow for inclusion of patients with TC1/2/3 or IC1/2/3 instead of TC3 of IC3. Co-primary endpoint of OS in addition to PFS endpoint was added. Stratification factors were modified. The timing of the primary PFS analysis and the definition of end of study were updated.

14 Mar 2017

Protocol was amended to exclude patients with a known sensitizing EGFR mutation or ALK translocation from the study. Investigator-assessed PFS was changed to a secondary endpoint and maintained OS as the primary endpoint. The secondary objective and outcome measure regarding independent review facility (IRF)-assessed PFS according to RECIST v1.1 have been removed. Modifications were made to the statistical testing procedure for the primary efficacy endpoint (OS). The sample size was changed from 570 to 555 patients.

16 Apr 2018

Protocol was amended to include modification of the number of OS events required in the TC2/3 or tumor-infiltrating IC2/3WT subgroup due to lower PD-L1 prevalence of TC2/3 or IC2/3-WT than the previous protocol assumption. Secondary endpoints to evaluate OS and PFS in patients with PD-L1 expression defined by the SP263 IHC assay and in patients with bTMB, including bTMB >=10, and bTMB >=16 were added.

29 Aug 2018

Protocol was amended to include modification to the timing of the interim efficacy analysis.

14 Mar 2019

Protocol was amended to include addition of the TC3 or IC3 population excluding patients with a sensitizing EGFR mutation or ALK translocation (i.e.; TC3 or IC3-WT) as the first testing hierarchy. The timing of the interim efficacy analysis was changed to be conducted when the prespecified criteria was met for the TC3 or IC3-WT population. The secondary endpoints for OS and investigator-assessed PFS in patients defined by the SP263 IHC assay were being updated to include the validated PD-L1 tumor expression cutoff of >=25% (in addition to >=1% and >=50%) in order to evaluate this additional PD-L1 expression level with respect to efficacy. The secondary endpoints for OS and investigator-assessed PFS in patients defined by the bTMB assay were being updated to include the 20 mutations cutoff (in addition to 10 and 16 mutations), in order to evaluate this additional TMB level with respect to efficacy. It was clarified that the primary safety analyses included all treated patients, defined as randomized patients who received any amount of study treatment, regardless of EGFR/ALK and PD-L1 status.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Primary: Overall Survival (OS) in the TC3 or IC3-WT Populations

Primary: Overall Survival (OS) in the TC3 or IC3-WT Populations

Primary: Overall Survival (OS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Primary: Overall Survival (OS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Progression-free Survival (PFS) in the TC3 or IC3-WT Populations

Secondary: Progression-free Survival (PFS) in the TC3 or IC3-WT Populations

Secondary: Progression-free Survival (PFS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Progression-free Survival (PFS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Percentage of Participants With Objective Response (ORR) in the TC3 or IC3-WT Populations

Secondary: Percentage of Participants With Objective Response (ORR) in the TC3 or IC3-WT Populations

Secondary: Percentage of Participants With Objective Response (ORR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Percentage of Participants With Objective Response (ORR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Duration of Response (DOR) in the TC3 or IC3-WT Populations

Secondary: Duration of Response (DOR) in the TC3 or IC3-WT Populations

Secondary: Duration of Response (DOR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Duration of Response (DOR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC3 or IC3-WT Populations

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC3 or IC3-WT Populations

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC2/3 or IC2/3-WT Populations

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC2/3 or IC2/3-WT Populations

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC1/2/3 or IC1/2/3-WT Populations

Secondary: Percentage of Participants Who are Alive at 1 and 2 Years in the TC1/2/3 or IC1/2/3-WT Populations

Secondary: Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Score as Assessed by the Symptoms in Lung Cancer (SILC) Scale Symptom Score in the TC3 or IC3-WT Populations

Secondary: Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Score as Assessed by the Symptoms in Lung Cancer (SILC) Scale Symptom Score in the TC3 or IC3-WT Populations

Secondary: Change From Baseline in Patient-reported Lung Cancer Symptoms Score as Assessed by the SILC Scale Symptom Score in the TC3 or IC3-WT Populations

Secondary: Change From Baseline in Patient-reported Lung Cancer Symptoms Score as Assessed by the SILC Scale Symptom Score in the TC3 or IC3-WT Populations

Secondary: TTD as Assessed Using EORTC QLQ Supplementary Lung Cancer Module (EORTC QLQ-LC13) in the TC3 or IC3-WT Populations

Secondary: TTD as Assessed Using EORTC QLQ Supplementary Lung Cancer Module (EORTC QLQ-LC13) in the TC3 or IC3-WT Populations

Secondary: OS in Participants with PD-L1 Expression

Secondary: OS in Participants with PD-L1 Expression

Secondary: Investigator-Assessed PFS in Participants with PD-L1 Expression According to RECIST v1.1

Secondary: Investigator-Assessed PFS in Participants with PD-L1 Expression According to RECIST v1.1

Secondary: OS in Participants with Blood Tumor Mutational Burden (bTMB)

Secondary: OS in Participants with Blood Tumor Mutational Burden (bTMB)

Secondary: Investigator-Assessed PFS in Participants with bTMB According to RECIST v1.1

Secondary: Investigator-Assessed PFS in Participants with bTMB According to RECIST v1.1

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab

Secondary: Percentage of Participants With at Least One Adverse Event

Secondary: Percentage of Participants With at Least One Adverse Event

Secondary: Percentage of Participants With Anti-therapeutic Antibodies (ATAs)

Secondary: Percentage of Participants With Anti-therapeutic Antibodies (ATAs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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